Critical analysis of glycosphingolipid pathways in aging and Parkinsons disease

衰老和帕金森病中鞘糖脂通路的批判性分析

• 批准号: 8941007
• 负责人: PENELOPE Jane HALLETT
• 金额: $ 31.11万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8941007
• 关键词: Acids; Affect; Aging; Biochemical; Biological Markers; Brain; Catabolism; Cell membrane; Cell physiology; Cells; Characteristics; Corpus striatum structure; Data; Development; Disease model; Endosomes; Enzymes; Epoxy Compounds; Fibroblasts; Functional disorder; Gaucher Disease; Gene Mutation; Genes; Genetic; Glucosylceramides; Glycosphingolipids; Grant; Health; Hippocampus (Brain); Homeostasis; Human; Hydrolase; Hydrolysis; In Vitro; Knowledge; Link; Lipids; Lysosomal Storage Diseases; Lysosomes; Measures; Membrane; Metabolism; Midbrain structure; Modeling; Modification; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Patients; Pharmacodynamics; Predisposition; Rattus; Reporting; Risk Factors; Rodent Model; Role; Testing; Therapeutic; Toxic effect; Transgenic Mice; Validation; alpha synuclein; design; disease stressor; dopaminergic neuron; gene therapy; genetic risk factor; glucosylceramidase; glucosylsphingosine; improved; in vitro testing; in vivo; in vivo Model; induced pluripotent stem cell; inhibitor/antagonist; neuropathology; neurotoxic; normal aging; novel; novel therapeutics; overexpression; prevent; public health relevance; research study; stressor; synucleinopathy

 DESCRIPTION (provided by applicant): Glycosphingolipids are essential for many cellular processes, are enriched in membranes, and undergo catabolism in endosomes and lysosomes through the action of acid hydrolases. GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), which is responsible for the hydrolysis of the glycosphingolipid substrates glucosylceramide (GluCer) and glucosylsphingosine (GluSph). GBA gene mutations are the highest known genetic risk factor for developing Parkinson's disease (PD) and related α-synucleinopathies. Our preliminary data shows that levels of GluSph are increased in the human brain in sporadic PD. Moreover, we show that GCase activity is reduced, and glycosphingolipid levels are increased in the brain in normal aging. The consequences of increased glycosphingolipid levels on neuronal health in aging and in sporadic PD are not known. In this R01 application I have designed experiments to test the relevance of elevated glycosphingolipids in neural cells in aging and PD. In Specific Aim 1 we hypothesize that altered levels of glycosphingolipids induce neuronal dysfunction and susceptibility to degeneration. We will modulate levels of GluSph in mouse and human neurons in vitro to determine whether neuronal vulnerability to PD-stressors, including increased α-synuclein loads, is altered. We will also establish whether reduced GCase and increased GluSph levels are detected in human PD patient fibroblasts and neurons as such alterations may represent novel bio- and pharmacodynamic- markers for PD. In Specific Aim 2 we hypothesize that reducing the accumulation of glycosphingolipids in aging and PD can prevent the aggregation and toxicity of α-synuclein. We will determine how the homeostasis of glycosphingolipid pathways are altered in two rodent models of α-synucleinopathy, and we will measure the effect of manipulating glycosphingolipid pathways by increasing neuronal GCase levels, in these same in vivo models. These experiments will provide critical analysis of the role of glycosphingolipid pathways in PD and related α-synucleinopathies, and should provide new targets for the development of novel therapeutics to improve glycosphingolipid metabolism and prevent neurodegeneration.

 描述(申请人提供)：糖鞘糖脂是许多细胞过程中必不可少的，富含在膜上，并通过酸性水解酶的作用在内体和溶酶体中进行分解代谢。GBA编码溶酶体的葡萄糖脑苷酶(GCase)，该酶负责糖鞘糖脂底物葡萄糖神经酰胺(GluCer)和葡萄糖鞘氨醇(GluSph)的水解。Gba基因突变是发生帕金森氏病(PD)和相关的α-突触核素病的最高已知遗传风险因素。我们的初步数据显示，散发性帕金森病患者大脑中GluSph水平升高。此外，我们还发现，在正常衰老的大脑中，GCase活性降低，糖鞘糖脂水平升高。在衰老和散发性帕金森病中，鞘糖脂水平升高对神经元健康的影响尚不清楚。在这个R01的应用中，我设计了实验来测试神经细胞中糖鞘糖脂升高与衰老和帕金森病的相关性。在特定的目标1中，我们假设糖鞘糖脂水平的改变会导致神经元功能障碍和变性的易感性。我们将在体外调节小鼠和人类神经元中GluSph的水平，以确定神经元对PD应激源的脆弱性是否发生了改变，包括增加的α-突触核蛋白负荷。我们会 此外，还确定在人类帕金森病患者的成纤维细胞和神经元中是否检测到GCase降低和GluSph水平升高，因为这种变化可能代表帕金森病的新的生物和药效学标记。在特定的目标2中，我们假设减少衰老和帕金森病中神经鞘糖脂的积累可以防止α-突触核蛋白的聚集和毒性。我们将确定在α-突触核病的两种啮齿动物模型中，神经鞘糖脂通路的动态平衡是如何改变的，我们将在这些相同的活体模型中，测量通过增加神经元GCase水平来操纵糖鞘磷脂通路的效果。这些实验将为神经鞘糖脂通路在帕金森病和相关的α-突触核病中的作用提供关键的分析，并将为改善神经鞘糖脂代谢和防止神经变性的新疗法的开发提供新的靶点。